Halogenated aryl alicyclic carboxylic acids and their salts and processes of manufacturing the same



Patented May 5, 1953 UNITED STATES PATENT OFFICE HALOGENATED ARYL ALICYCLIC CARBOX- YLIC ACIDS AND THEIR SALTS AND PROC- ESSES OF MANUFACTURING THE SAME New Jersey No Drawing. Application April 19, 1948, Serial No. 21,853

14 Claims. 1

The present invention relates to the manufacture of halogenated aryl alicyclic alkene and alkane carboxylic acids and their metal and amine salts.

It is a general object of the invention to produce halogenated compounds having useful chemotherapeutic properties. Other objects of the invention will appear as the more detailed description thereof appears.

We have found that in general the A -cycloalkene substituted acetic acid and the homologous acids and the corresponding isomeric cycloalkylidene carboxylic acids, having in the 11-position to the carboxylic group either a methylene radical or the group :CI-I (in the case of acetic acid), for example cyclohexenyl, cyclohexylidene, cyclopentenyl, cyclopentylidene, dihydronaphthyl and analogous acetic acids, and likewise the members of the acetic acid series substituted by terpene or terpene-like radicals having a double bond connected to the nuclear carbon linked to the acid group, can be condensed with a hydroxy aldehyde wherein the double bond of the aldehyde group forms part of a conjugated double bond system, the phenyl nucleus containing or being free from halogen atoms, to form dicyclic alkene carhoxylic acids which may be subsequently saturated in the alkene chain and in the cycloalkene ring; and these products are treated with halogenating agents if none of the I starting compounds contained halogen. Among the starting'aldehydes may be mentioned hydroxy benzaldehydes, hydroxy-iodo-benzaldehydes, hydroxybromo-benza1dehydes, hydroxychloro-benzaldehydes, and the corresponding cinnamaldehydes.

As just indicated, the compounds of the present invention may be produced either by the halogenation of the aryl alicyclic alkene and alkane carboxylic acids having a hydroxyl-substituted benzene radical, or by forming the dicyclic compounds from starting compounds which already contain halogen. In the first procedure compounds which may be produced in accordance with the process described in our copending application entitled Aryl-Alicyclic Carboxylic Acids and Process for Their Manufacture, Serial No. 544,831, filed July 13, 1944, are subjected to a known halogenation treatment. In proceeding in accordance with the second mode of manufacture, halogenated aromatic aldehydes,

for example 3,5-diiodo-4-hydroxy-benzaldehyde, or the corresponding cinnamaldehyde, may be condensed with cycl oalkene carboxylic acids or the corresponding cycloalkylidene carboxylic acids (in the form of their alkali metal salts).

Thus in making the compounds of the invention by the first-mentioned procedure, p-hydroxybenzaldehyde may, for example, be condensed by the Perkin reaction, or by modifications of the Perkin reaction, with a salt of cyclohexenyl acetic acid, such as the potassium or sodium salt, under anhydrous conditions in the presence of acetic anhydride, or in the form of the free acid and with the aid of a catalyst, for example, a tertiary amine like triethyl or tributyl amine, and the resulting a(A -cyc1ohexenyl)-p-hydroxycinnamic acid may then be carefully hydrogenated, as by means of hydrogen and Raney nickel catalyst, and thereafter iodinated by known reagents to yield a-OYCIO- hexy ,8 (3,5-diiodo 4 hydroxyphenyDpropionic acid according to the following equation:

I 0110 moooH I Hz-l-Iz I I In the alternative procedure, by employing, for example, 3,5-diiodol-hydroxybenzaldehyde as one of the starting materials, the compound OOH group is part of a conjugated double bond system.

The invention will be further described with the aid of the following examples-which arenpresented only for purposes ofillustration:

EXAMPLE I:

a-(A cyclohemenyl) 3,5 dz'iodo-4-hydroamcinnamic acid.

A mixture of 17.9 g. of anhydrous potassium cyclohexylidene acetate, 37.4 g. of! 3,5-diidQQ-4r hydroxybenzaldehyde and 100 cc. of acetic anhydride is heated for 20-30 hours at 105-110, C. The condensation is run under anhydrous conditions. After the, reaction mixture has cooled to about 60 C. the excess acetic anhydride is decomposed cautiouslywith water and the reaction mixture poured onice. The semi-solid residue is extracted with ether and the acidic fraction isolated by meansof sodium carbonate extraction. The sodium carbonate extracts are freed of ether, cooled and acidified to Congo red paper'with H01. The pale-yellow precipitate is then recrystallized from a mixture of water and acetoneand't'heisubstituted cinnamic acid is obtained in the form of a very'pale yellow solid, melting at 212 C. withdecomposition.

EXAMPLE II a- (n -cyclohczce-nyl) 3'-z'odocinnamic acid.

EXAMPLE III [:3- (3,5 -diiodo-4-hydroazypheny-Z) acyclohemylpropiom'c acid This acid is prepared by first condensing p-hydroxybenzaldehyde and anhydrous potassium cyclohexylideneacetate in acetic anhydride, The resulting a(A -cyclohexenyl).-4-hydroxycinnamic 301G115; reduced by any of the standard methods, and the hydrogenatedcompound iodinated asziollows: To 0.1 m. (24%) of this hydrogenated aciddissolved in 800.cc. of.

sodium hydroxide there is added a solution of 4 4 obtained in a yield of 50 g., melting at -146 C. Recrystallization from acetone and water gives a product melting at -156 C.

EXAMPLE IV {34 3,5-diiodmkhydroxyphenyl) -a.- cyclopentylpropionic. acid 23.4 g. (0.1 m.) of a-(cyclopentyb-p-(p-hydroxyphenyllpropionic acid is iodinated as described'inExample III. The B-(3,5-diiodo-4-hydroxyphenyl)I-a=cyclopentylpropionic acid is obtained in the form of a white crystalline powder which on: recrystallization from acetone-water mixture melts at 131-132 C.

EXAMPLE V In similar fashion, a-(3,4-dihydro-6-methoxy- (a) naphthyl) -3,5-diiodo 4 hydroxycinnamic acid ,is-obtained by reacting the potassium salt of 3,4-dihydro-6-methoxy- (a) -naphthylacetic acid with 3,5-diiodoi-d-hydroxybenzaldehyde in. the presence of acetic anhydride. The product isisolated as describedin Example I and after recrystallization from chloroform-petroleum ether melts at 112-114" C. with decomposition.

The syntheses as outlined in Examples I to V can be modified to avoid the. use of the anhydrous alkali salts; This modification uses the free acid, cyclohexenyl, cyclopentenyl, and other alicyclic acetic acids with'the appropriate aromaticaldehyde together with suitable. catalystsi. e.,v triethyl amine, anhydrous sodium or potassium acetate, anhydrous potassium carbonate, etc.

28. g. (0.2-m.) of cycloexenylacetic acid, 24.4 g. (0.2 m.) of p-hydroxybenzaldehyde, 20.2 g. (0.2 m.) of triethylamine and 61.2 g. (0.6 m.). ofacetic anhydridev are heated for 10-12 hours at 100-120" C. The reaction mixture is worked up as, describedv above, yielding a-(n -cyclohexenyD-r hydroxycinnamio acid which is then iodinated to the 8,5-diiodo-4-hydroxy compound.

The. corresponding aliphatically compound of the formula saturated can-be prepared lay-first reacting anhydrous-p0- tassium 3,4-dihydro-6-methoxy e-naphthyl' acetate with 4-hydroxybenzaldehyde, followed by hydrogenationof the alicyclic ring and of the aliphatic chain, after which the intermediateds subjected to 'iodination,

In similariashion; by the iollowing serieszoi reactions a- 3 isopropyl+6-methyhAl-cyolohexeenyl) -3,5-diiodo-4-hydroxycinnamicn acid (I) and. o.v( 3iisopropyhfiemethylcyclohexyl) .-.fi. diiodos4ehydroxyphenyl). propionicz acid; (119: can be prepared :from the corresponding .ter.penez.cam=

5 pounds and diiodo-hydroxy and hydroxybenzaldehyde respectively:

on, OH

cmooon I I on 0H0 H C C s OH:

I o=onon JJOOH f 0H3 CH3 cm on 011100011 Q Hmnd 011 $110 Ha CH: CH

I (IJHCH2Q'OH coon r 011; CH;

EXAMPLE VII a-CZIClOhJJIUl-fl- (3,5-dibromo-4-hydroa:yphenyl) propionic acid To a solution 010.1 m. of a-cyclohexyl-p-(phydroxyphenybpropionic acid in 159 cc. of acetic acid there is added dropwise with st1rr1ng, a-solution of 16 g. of bromine in 50 cc. of acetic acid. The reaction mixture is allowed to stand overnight, then diluted with water, and the crude dibromo acid filtered or isolated by ether extraction. Recrystallization from aqueous ethanol leaves the dibromo acid as a white crystallme solid melting at 158160 C.

EXAMPLE VIII c-CycZohewyZ-B-(3,5-dichZoro-4-hydroxyphenyl) propionic acid I This compound is prepared in accordance W1 the instructions of Example VII, except that 7.1 g. of chlorine dissolved in 100 cc. of acetic acid 18 substituted for the bromine solution. The d1- chloro acid after recrystallization from aqueous ethanol melts at 173.5-1745 C.

EXAMPLE IX (2- (N-cyclohexenyl) -3,5-dichloro-4-hydroxycinnamic acid x ure of 0.1 m. of cyclohexanol-l-acetic ac it i l l m. of 3,5-dichlorofl-hydroxybenzaldehyde, 0.3 m. of anhydrous triethylamme and 15% cc. of acetic anhydride is heated for 72 hours a 105-110 C. The reaction mixture is then worked up as described with the correspondm g dnodo compound and purified by recrystall zation frgrr: benzene-petroleum ether, melting point 194-1 o EXAMPLE X a-(A -cyclohexenyl) 3 -chloro 4 hydroxycz'm namic acid EXAMPLE XI a-CycZopentyZ-B- (3,5 -dibromo-4-hydroacyphenyDpropionz'c acid a-Cyclopentyl ,8 (p-hydroxyphenyl) propionic acid is brominated exactly as described for the homologous cyclohexyl compound. It may be recrystallized from aqueous alcohol or a mixture of chloroform and petroleum ether.

The condensation products above described may be prepared in the form of various salts, such as the sodium, potassium, calcium, magnesium and other metal salts, by the conventional methods of neutralization or double decomposition. The amine salts, such as the diethyl amino ethanol salt, the mono-, di-, and triethanol amine salts and likewise the salts of other nontoxic amines can be prepared by combining equimolecular proportions of the substances in suit-- able solution followed by precipitation or crystallization.

The compounds of the invention possess bactericidal and amebicidal properties and are particularly useful in the treatment of amebic infections of the alimentary tract as their bactericidal properties aid in alleviating the secondary bacterial infections which are a common concomitant of amebiasis. The iodine-containing compounds of the invention are also useful as X-ray contrast agents, and they are particularly valuable for oral administration for cholecystographic examination. They are substantially less toxic than the contrast agents heretofore available for X-ray examination of the gall bladder and they have the additional advantage that their bactericidal activity is useful in combating infections of the gall bladder so that they possess a double utility when employed as contrast agents.

In the specification and claims the terms halogen and halogenated are intended to denote chlorine, bromine and iodine.

This application is a continuation-in-part of our application Serial No. 544,832, filed July 13, 1944, and contains subject matter in common with our applications Serial No. 629,916, filed November 20, 1945, Serial No. 722,084, filed January 14, 1947, and Serial No. 784,310, filed November 5, 1947.

We claim:

1. A member of the group consisting of acids of the formula and their non-toxic salts, R being an alicyclic radical having from 5 to 6 carbon atoms in the ring, Z being an m-halogeno-p-hydroxy-phenyl radical, the halogen being selected from the group consisting of chlorine, bromine and iodine, and Y being a saturated aliphatic chain of 2 carbon atoms, to different carbons of which the radicals R and Z are directly attached, the carboxylic group being attached to the same carbon as the alicyclic group.

2. a-Alicyclic fi- (3;5-diiodo i hydroxy-phenyl) propionic acids, the alicyclic ring having from 5 to 6 carbon atoms;

3. a-CYClOhBXYl- B 3,5-dibromo 4 hydroxyhenylrpropionicacid; V

4'; iz-Cyclohexyl e: (aS-diciiibro-A-hydi caiy phenylj'propionicacid. H

6. Process for the manufacture of dicyclically substituted aliphatic carboxylic acids, which comprises heating and condensing a member of the group consisting of alicyclically substituted acetic acid'sand-their saltsowherem the l carbon of' the alicyclicring has a double bond connected thereto; and-whereinthdalicyclic-rirlghas from 5" to 6 carbon atoms, with ap iiydroxy benzene aldehyde under susbtantiaily anhydrous conditions andin the presence-oi the-'anhydiide of a lower" fatty acidto produce an alicyclic'ally and aromatically substituted alkene carboxylic acid c hydrogenating the" non-henzenoid double bondsiof the condensation product, and reacting the resulting product with a halogenating agent to-intro ducehalogen intothe "aromatic ring;

7. Process: for the: manufacture of dicyclicallysubstituted aliphatic carboxylic acidswhich com prises heating and condensing a salt of cycle hexylidene acetic acid;.with' a p-hyidroxybenzene aldehyde under substantially anhydrouscondiw ti'ons and'in' thepi'esence'ofthe anhydriderof a lower-fatty acid to'produce an alicyclically' and aromaticallyi substituted -alkene carboxylic acid, hydrogenati'ng. the non-benzenoid double: bonds of the condensation product, and reacting the resulting product with a' halogenating agent to introducehalogen into thcaromatic ring;

8 Process for' the'manufacture of dicyclically substituted aliphatic carboxylic acids, which comprises. heatingand condensing a member of the group consistingnof alicyclically substituted a'cetic acids and their salts, whereinthe l-carbon oi the alicyclicring; hasa double' bondconnected thereto, and wherein i the alicyclic ring has from 5' to: 6 i carbon: atoms;v with p-hydrcxybenzene aldehyde under" substantially anhydrous: conditions:and in the presence of-the-anhydrideof a lower fatty acid to produce an alicyclically'zm'd arom'atically substituted alirene carboxyl'ic acid,

l-iydro'genatin gz: the non-benzenoid double bonds of the condensation product; and reactin'gz the resulting: product with an iodinatingagent to introduce iodine into" the aroma-tic" ring;

9; Process for the manufacture of dicyclica'lly substituted aliphatic-carboxylicacids which oom+ prises heating and condensing; a salt of cycle hexyiidene- *acetic acid; with a'p -hydro'xybenzene aldehyde under substantially anhydrous co'ndi tions and in the presence of the anhydridaoi a lower fatty acitl to producean alicycii'cally" mu aromatically substituted aliefle cairboxy-lic a'cld; hydrogenating the non-benzenoid double bonds of the condensation product, and reacting the resulting product With- 31i iodinating agent to introduce iodine into the aromatic ring.

10. Compounds of the formula Hal Hal H81 Hal ('3 H:C H.cyc1opentyl coon wherein Hal is a: halogen of atomic number not less than 17 and' n'ot-more than 53.

13. A member of the group consisting of acids of the formula wherein Hal-is-aahalogen-of atomic number not less thanv L7 and not more-than 53'"and"R is an.

alicyclic radical havingirom fi-to carbon-atoms 1n the ring, {and the non toxic salts thereof;

14'. -Cyciopentyl 5- 3;5-dibromo-4-hydro:iy'-

phcnyl) pmpicnic acid: 

1. A MEMBER OF THE GROUP CONSISTING OF ACIDS OF THE FORMULA 